Cancer Genetics and Epigenetics 2024, Vol.12, No.5, 294-305 http://medscipublisher.com/index.php/cge 298 4.2 Enhancing immunotherapy by editing immune cells (e.g., T Cells, NK Cells) Gene editing technologies are also being applied to enhance the efficacy of immunotherapies for ovarian cancer by modifying immune cells such as T cells and natural killer (NK) cells. CRISPR-Cas9 has been used to knock out genes that encode inhibitory immune checkpoints, such as PD-1, on T cells, enhancing their ability to attack and destroy ovarian cancer cells. For instance, gene editing of PD-1 in T cells has shown promise in improving immune responses against tumors by preventing tumor immune evasion (Panda et al., 2019). NK cells have also been genetically modified to improve their tumor recognition and killing abilities by removing inhibitory receptors, which normally prevent them from attacking cancer cells. These modifications aim to boost the immune system's natural ability to target and eliminate ovarian tumors. Enhancing the efficacy of immune cells through gene editing is a promising area of research that has the potential to improve the success rate of immunotherapy in ovarian cancer. 4.3 CRISPR-mediated knockout of oncogenes in ovarian tumor models CRISPR-Cas9 has been instrumental in creating more accurate models of ovarian cancer by enabling the targeted knockout of oncogenes. In ovarian cancer research, CRISPR has been used to knock out key oncogenes such as TP53, BRCA1, and BRCA2, providing insight into how these genes drive tumor growth and resistance to chemotherapy (Yahya et al., 2022). For example, in one study, CRISPR-Cas9 was used to knock out TP53 and BRCA2 in murine models of high-grade serous ovarian carcinoma (HGSC), leading to the development of tumors that closely mimic human ovarian cancer. These models were critical for studying the impact of gene mutations on chemotherapy sensitivity and immune cell infiltration into tumors (Walton et al., 2016) (Figure 1). Additionally, targeting other oncogenes like FOXM1, which promotes tumor proliferation, has been shown to slow tumor growth and improve responses to chemotherapy in ovarian cancer cells (Tassi et al., 2017). These gene knockouts offer promising therapeutic avenues by identifying critical drivers of ovarian cancer. 4.4 Restoring function of tumor suppressor genes in ovarian cancer cells Restoring the function of tumor suppressor genes is another critical focus of gene editing research in ovarian cancer. CRISPR-Cas9 has been used to repair or reactivate tumor suppressor genes, such as TP53 and BRCA1, which are often inactivated in ovarian cancer due to mutations. One innovative approach involves using CRISPR-dCas9 to target and demethylate hypermethylated promoters of tumor suppressor genes, effectively restoring their expression and tumor-suppressing functions. For example, CRISPR-dCas9-mediated targeting of the BRCA1 promoter led to selective DNA demethylation, which restored gene expression and reduced tumor growth (Choudhury et al., 2016). This approach not only highlights the versatility of CRISPR technology but also its potential in reactivating silenced tumor suppressor genes. Restoring the function of tumor suppressors through gene editing offers a promising strategy to halt cancer progression and enhance the efficacy of existing therapies. 5 Challenges and Limitations in Applying Gene Editing to Ovarian Cancer 5.1 Precision in editing ovarian cancer-specific genes While gene editing technologies such as CRISPR-Cas9 offer immense potential for ovarian cancer research and therapy, several challenges must be addressed. These challenges encompass issues related to the precision of gene targeting, ethical concerns, efficient delivery of editing tools, and tumor heterogeneity that leads to resistance. One of the most critical challenges in applying gene editing to ovarian cancer is achieving precise modifications at target loci without causing off-target effects. Ovarian cancer involves numerous mutations, some of which are specific to particular tumor subtypes. Ensuring precision in editing ovarian cancer-specific genes, such as BRCA1, BRCA2, and TP53, is essential to avoid unintended alterations that could exacerbate tumorigenesis or create new mutations. For instance, the non-homologous end joining (NHEJ) repair pathway, commonly triggered by CRISPR-Cas9-induced DNA breaks,
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